The amyloidoses are a group of pathological conditions in which normally soluble proteins polymerize to form insoluble amyloid fibrils and amyloid deposits. More than 15 proteins form amyloid fibrils resulting in diverse clinical conditions. Amyloidoses are usually classified into systemic amyloidoses and localized amyloidoses. Major systemic amyloidoses include AL amyloidosis, amyloid A amyloidosis, and familial transthyretin amyloidosis; the corresponding amyloid proteins in these amyloidoses are AL amyloid, amyloid A protein, and transthyretin, respectively. Prominent localized amyloidoses include Alzheimer's disease, prion diseases, and type II diabetes; the corresponding amyloid proteins in these diseases are amyloid β peptide, scrapie prion protein, and human amylin, respectively (Sipe (1992) Annu. Rev. Biochem. 61:947–975).
Amyloid or amyloid proteins refer to a group of diverse extracellular proteins that form amyloid deposits with common morphological, ultrastructural and physicochemical properties. For example, amyloid deposits have similar affinities for certain dyes and a characteristic appearance under polarized light. Although they vary in amino acid sequence, all amyloid proteins found in amyloid deposits consist of aggregations containing interlacing bundles of parallel arrays of fibrils where the protein in the fibrils is organized in a β-pleated sheet structure.
Amyloidoses share several common features, indeed all are related to amyloid deposits formed by amyloid proteins having different amino acid sequences. For example, many of the amyloid proteins in amyloid deposits are rich in β-pleated sheet conformation, which is responsible for the intensely increased birefingence of amyloid fibrils following Congo red staining (Glenner et al., (1974) J. Histochem. Cytochem 22:1141–1158; Glenner and Page (1976) Int. Rev. Exp. Pathol. 15:1–92; Glenner (1980) N. Engl. J. Med. 302:1283–1292 (Pt. 1) and 133–1343 (Pt. 2)).
Amyloid fibrils, regardless of the amyloid protein from which they are formed, have a cytotoxic effect on various cell types including primary cultured hippocampal neurons (Yankner et al. (1990) Science 250:279–282), pancreatic islet β cells (Lorenzo et al. (1994) Nature 368:756–760) and clonal cell lines (Behl et al. (1992) Biochem Biophys. Res. Commun. 186:944–952; O'Brien et al., (1995) Am. J. Pathol. 147:609–616). In fact, only amyloid proteins in fibrillar form are cytotoxic (Pike et al. (1991) Brain Res. 563:311–314; Lorenzo and Yankner (1994) Proc. Natl. Acad. Sci. 91:12243–12247). It is likely that the cytotoxic effect of fibrils is mediated by a common mechanism (Lorenzo and Yankner (1994) id.; Schubert et al. (1995) Proc. Natl. Acad. Sci. USA 92:1989–1993).
Modulation of amyloid protein aggregation is one means of blocking or reducing amyloid toxicity. A detailed description of such modulatory methods can be found in U.S. Pat. No. 5,854,204 (issued Dec. 29, 1998) which is incorporated herein by reference in its entirety.
There is thus a need for additional methods for blocking amyloid protein production and for blocking amyloid toxicity. In particular there is a need for blocking amyloid beta peptide toxicity in neurons, inhibiting the production of amyloid beta peptide, and blocking the production of various other cytotoxic amyloid proteins that result in disease conditions.